VEGFA165 gene therapy ameliorates blood-labyrinth barrier breakdown and hearing loss

Abstract

Millions of people are affected by hearing loss. Hearing loss is frequently caused by noise or aging, and often associated with loss of pericytes. Pericytes populate small vessels in the adult cochlea. However, their role in different types of hearing loss is largely unknown. Using an inducible and conditional pericyte depletion mouse model and noise-exposed mouse model, we show that loss of pericytes leads to marked changes in vascular structure, leading, in turn, to vascular degeneration and hearing loss. In vitro, using advanced tissue explants from pericyte fluorescence reporter models combined with exogenous donor pericytes, we show pericytes, signaled by endothelial growth factor isoform A165 (VEGFA165), vigorously drive new vessel growth in both adult and neonatal mouse inner ear tissue. In vivo, the delivery of an adeno-associated virus serotype 1 (AAV1)-mediated VEGFA165 viral vector to pericyte depleted or noise-exposed animals prevented and regenerated lost pericytes, improved blood supply, and attenuated hearing loss. These studies provide the first clear-cut evidence pericytes are critical for vascular regeneration, vascular stability, and hearing in adults. Restoration of vascular function in the damaged cochlea, including in noise-exposed animals, suggests that VEGFA165 gene therapy could be a new strategy for ameliorating vascular associated hearing disorders.

Pericytes control vascular stability and auditory spiral ganglion neuron survival

“…3A , we found the control mice showed no significant hearing threshold change after DT injection. In contrast, the hearing threshold in pericyte-depleted animals was significantly elevated at 1 week after DT injection and persisted to two weeks after DT injection (n=10, P<0.0001, two-way ANOVA), consistent with our previous observation (Zhang et al, 2021).…”

“…To investigate whether pericyte loss affects vascular stability in the spiral ganglion in adult mice, we created an inducible pericyte depletion mouse model ( Pdgfrb CreERT+/- ; R26 iDTR+/- ) by crossing Pdgfrb CreERT2+/- transgenic mice with ROSA26 iDTR+/+ mice, an inducible daiphtheria toxin receptor (iDTR) mouse line carrying Cre-dependent simian DTR, which leads to cell death with the administration of the diphtheria toxin (DT) (Buch et al, 2005; Zhang et al, 2021) (as illustrated in Fig. 2A ).…”

“…This Pdgfrb CreERT+/- ; R26 iDTR+/- mouse line at one month of age received tamoxifen (TAM) for three days to induce the expression of Cre recombinase. For ablation of pericyte, DT was administrated by daily intraperitoneal injection at 10 µg/kg for 4 consecutive days beginning 1 day after TAM (Zhang et al, 2021) (as illustrated in Fig. 2B ).…”

Hearing Function, Degeneration, and Disease: Spotlight on the Stria Vascularis

“…Within the cochlea, pericytes contribute to angiogenesis (the formation of new blood vessels), vascular integrity, and blood flow control (Reviewed in Caporarello et al, 2019). Pericyte depletion (in a Cre-mediated diphtheria toxin inducible mouse model) causes reduced vascular density, variable vessel size, vascular leakage, and hearing loss (Zhang J et al, 2021). Notably, RTqPCR and immunohistochemical analysis indicated that vascular endothelial growth factor isoform A165 (VEGFA165) is particularly important for pericyte function.…”

Role of the Stria Vascularis in the Pathogenesis of Sensorineural Hearing Loss: A Narrative Review

“…Another important function of the SV is to regulate the secretion of the endolymph and maintain cochlear homeostasis (Taukulis et al, 2021;Zhang et al, 2021). Among these, H(+) -ATPase (ATP6V1B1 and ATPV0A4) and bicarbonate/chloride transporter SLC26A4 (Pendrin) are expressed in the SV, and regulate the secretion of H+ and HCO3− in the endolymph to maintain pH homeostasis (Mittal et al, 2017); similarly, the Ca(2+) -ATPase and Ca(2+) channels expressed in the SV jointly maintain Ca(2+) homeostasis in the endolymph (Nin et al, 2016).…”